A large and growing number of people suffer from diabetes mellitus and obesity. Diabetes mellitus is a metabolic disorder in which the ability to utilize glucose is partly or completely lost.
A number of treatment regimes are targeting excessive blood glucose whereas others are focused primarily on weight reduction. The most efficient anti-diabetic agent used to lower blood glucose is insulin and analogue(s) thereof. It has been known for a long time that when traditional insulin is used to treat diabetes, it is associated with an increase in body weight. Insulin has to be injected subcutaneously up to several times per day.
Type 2 diabetes is generally treated in the early phases with diet and exercise. As the condition progresses, various oral anti-diabetic agents are added. Injected agents such as GLP-1 analogues may also be used at this stage. In general, these agents are most efficient in patients with functioning beta-cells capable of releasing insulin and amylin.
Human amylin is a 37 amino acid long peptide which has physico-chemical properties that make its use as a drug troublesome. In particular, it has a tendency to fibrillate invitro and/or ex-vivo and become ineffective due to precipitation. Additionally amylin is difficult to formulate as it precipitates at physiologic pH. Therefore it is formulated in a acidic solution.
A drug product sold under the trademark Symlin® is currently on the market. The product contains an analogue of human amylin called pramlintide. Compared to human amylin the amino acids in position 25, 28 and 29 in pramlintide are substituted with proline. This modification reduces the fibrillating tendency of the protein. Pramlintide is difficult to keep in solution at neutral pH and it is therefore provided in an acidic solution i.e. Symlin®. Another disadvantage is that Symlin has to be injected at separate injection site three times daily.
International patent application no. EP2008/062036 discloses amylin derivatives having an albumin binding residue. Even though the amylin derivatives shows improved pharmacokinetic (PK) or pharmacodynamic (PD) properties compared to pramlintide they still tend to fibrillate and are difficult to keep in solution at pH 4.